دورية أكاديمية
Self-assembled GLP-1/glucagon peptide nanofibrils prolong inhibition of food intake.
| العنوان: | Self-assembled GLP-1/glucagon peptide nanofibrils prolong inhibition of food intake. |
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| المؤلفون: | Ouberai MM; Nanoscience Centre, Department of Engineering, University of Cambridge, Cambridge, United Kingdom., Gomes Dos Santos AL; Advanced Drug Delivery, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom., Kinna S; Nanoscience Centre, Department of Engineering, University of Cambridge, Cambridge, United Kingdom., Hornigold DC; Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom., Baker D; Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom., Naylor J; Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Liang L; Cardiovascular, Renal and Metabolic Diseases, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom., Corkill DJ; Bioscience In Vivo, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals, R&D, AstraZeneca, Cambridge, United Kingdom., Welland ME; Nanoscience Centre, Department of Engineering, University of Cambridge, Cambridge, United Kingdom. |
| المصدر: | Frontiers in endocrinology [Front Endocrinol (Lausanne)] 2023 Jul 24; Vol. 14, pp. 1217021. Date of Electronic Publication: 2023 Jul 24 (Print Publication: 2023). |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101555782 Publication Model: eCollection Cited Medium: Print ISSN: 1664-2392 (Print) Linking ISSN: 16642392 NLM ISO Abbreviation: Front Endocrinol (Lausanne) Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: [Lausanne : Frontiers Research Foundation] |
| مواضيع طبية MeSH: | Glucagon*/metabolism , Glucagon-Like Peptide 1*/pharmacology, Eating/physiology ; Oxyntomodulin/chemistry ; Oxyntomodulin/pharmacology ; Peptide Hydrolases ; Peptides/pharmacology ; Receptors, Glucagon/metabolism ; Animals |
| مستخلص: | Introduction: Oxyntomodulin (Oxm) hormone peptide has a number of beneficial effects on nutrition and metabolism including increased energy expenditure and reduced body weight gain. Despite its many advantages as a potential therapeutic agent, Oxm is subjected to rapid renal clearance and protease degradation limiting its clinical application. Previously, we have shown that subcutaneous administration of a fibrillar Oxm formulation can significantly prolong its bioactivity in vivo from a few hours to a few days. Methods: We used a protease resistant analogue of Oxm, Aib2-Oxm, to form nanfibrils depot and improve serum stability of released peptide. The nanofibrils and monomeric peptide in solution were characterized by spectroscopic, microscopic techniques, potency assay, QCM-D and in vivo studies. Results: We show that in comparison to Oxm, Aib2-Oxm fibrils display a slower elongation rate requiring higher ionic strength solutions, and a higher propensity to dissociate. Upon subcutaneous administration of fibrillar Aib2-Oxm in rodents, a 5-fold increase in bioactivity relative to fibrillar Oxm and a significantly longer bioactivity than free Aib2-Oxm were characterized. Importantly, a decrease in food intake was observed up to 72-hour post-administration, which was not seen for free Aib2-Oxm. Conclusion: Our findings provides compelling evidence for the development of long-lasting peptide fibrillar formulations that yield extended plasma exposure and enhanced in vivo pharmacological response. Competing Interests: Authors AG, DH, DB, JN, LL and DC were employed by AstraZeneca. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2023 Ouberai, Gomes Dos Santos, Kinna, Hornigold, Baker, Naylor, Liang, Corkill and Welland.) |
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| فهرسة مساهمة: | Keywords: GLP-1/glucagon; depot formulations; metabolic diseases; nanofibrils; peptides; self-assembly |
| المشرفين على المادة: | 9007-92-5 (Glucagon) 89750-14-1 (Glucagon-Like Peptide 1) 0 (Oxyntomodulin) EC 3.4.- (Peptide Hydrolases) 0 (Peptides) 0 (Receptors, Glucagon) |
| تواريخ الأحداث: | Date Created: 20230809 Date Completed: 20230810 Latest Revision: 20230814 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC10406450 |
| DOI: | 10.3389/fendo.2023.1217021 |
| PMID: | 37554763 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1664-2392 |
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| DOI: | 10.3389/fendo.2023.1217021 |